4(Quinolyl)phenoxy alkanoic acid derivatives

ABSTRACT

Phenoxyacetic acids of the formula ##SPC1## 
     Wherein R 1  is H or alkyl of 1-4 carbon atoms; R 2  is H, or when R 4  is Q, also alkyl of 1-4 carbon atoms; R 3  is methyl, phenyl or chlorophenyl; and R 4  is piperidino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1-R 5  -1,2,3,4-tetrahydro-4-quinolyl, 4-piperidinophenyl, 4-piperidinophenoxy, 1-pyrryl, or Q, wherein R 5  is H or alkyl of 1-4 carbon atoms; and Q is 4-oxo-1,2,3,4-tetrahydroquinolino, 4-hydroxy-1,2,3,4-tetrahydroquinolino, 4-chromanyl, 4-thiochromanyl or 1-phenyl-1,2,3,4-tetrahydro-4-quinolyl; and the salts thereof, possess cholesterol level-lowering activity.

BACKGROUND OF THE INVENTION

This invention relates to novel phenoxyacetic acid derivatives.

SUMMARY OF THE INVENTION

The novel compounds of this invention are phenoxyacetic acid derivativesof the Formula I ##SPC2##

wherein R₁ and R₅ each are H of alkyl of 1-4 carbon atoms; R₂ is H, orwhen R₄ is Q, H or alkyl of 1-4 carbon atoms; R₃ is methyl, phenyl orchlorophenyl; and R₄ is piperidino, isoindolinno,1,2,3,4-tetrahydroquinolino, 1-R₅ -1,2,3,4-tetrahydro-4-quinolyl,4-piperidinophenyl, 4-piperidinophenoxy, 1-pyrryl, or Q, wherein R₅ is Hor alkyl of 1-4 carbon atoms and Q is 4-oxo-1,2,3,4-tetrahydroquinolino,4-hydroxy11,2,3,4-tetrahydroquinolino, 4-chromanyl, 4-thiochromanyl or1-phenyl-1,2,3,4-tetrahydro-4-quinolyl, and the physiologicallyacceptable salts thereof with acids or bases.

DETAILED DISCUSSION

The class of compounds of Formula I comprise compounds of Formulae Iathrough Ig (wherein R₁, R₂ and R₃ have the values given above): ##SPC3##

More particularly, compounds of Formulae I and Ia through Ig includethose wherein

Ih. R₁ is H, CH₃ or C₂ H₅ ;

Ii. R₂ is H or CH₃, especially those of Ih;

Ij. R₃ is CH₃, C₆ H₅, m-chlorophenyl or p-chlorophenyl, preferably C₆ H₅or p-chlorophenyl, especially those of Ih and Ii.

Compounds of Formulae Ic, Id, If and Ig, particularly those defined inIh, Ii and Ij above, are especially valuable from a pharmaceuticalviewpoint.

In its process aspect, this invention relates to a process for theproduction of compounds of Formula I, as well as the physiologicallyacceptable salts thereof with acids or bases, wherein:

A. A PHENOL OF GENERAL Formula II ##SPC4##

wherein R₄ has the values given for Formula I, is reacted with acompound of general Formula III

    x-cr.sub.2 r.sub.3 -coor.sub.1 iii

wherein X is Cl, Br, I, OH or esterified OH and R₁, R₂ and R₃ each havethe values given for Formula I, or is reacted together with a haloformand a carbonyl compound of the general formula R₂ --CO--R₃ (wherein R₂and R₃ have the values given for Formula I); or

b. a compound of general Formula IV ##SPC5##

wherein Z is Z_(1--Y) ₁ --NH--(A₁)_(n) -, Z₂ --CH₂ CH₂ -N(C₆ H₅)--, C₆H₅ -Y₂ -CH₂ CH₂ -CHX-, or HY₂ -(o-C₆ H₄)-CH(CH₂ CH₂ X)-,

Y is pentamethylene or o-xylylene, Z₁ is Cl, Br, I, NH₂, OH, or anesterified or etherified OH-group, Z₂ is a free COOH-group, or aCOOH-group present in the form of a functional derivative, Y₂ is O, S orNC₆ H₅, and R₁, R₂, R₃, A₁ and n have the values given above, is reactedwith a cyclizing agent; or

c. in a compound of general Formula V ##SPC6##

wherein W is a functionally modified carboxyl group which is differentthan COOR₁, and R₂, R₃ and R₄ have the values given above, the group Wis converted into the group COOR₁ by treatment with a solvolyzing agent;or

d. a compound of general Formula VI

    r.sub.4 - x.sub.1 vi

wherein X₁ is H, M or X; M is an equivalent of a metallic atom, and R₄and X have the values given above, is reacted with a compound of generalFormula VII ##SPC7##

wherein X₂ is H, Cl, Br, I, NH₂ or SO₃ M, and M, R₁, R₂ and R₃ have thevalues given above, with the provision that X₁ and X₂ are not alike andone is H or optionally M; or

e. a compound of general Formula VIII ##SPC8##

wherein Y₂, R₁, R₂ and R₃ have the values given above, is reduced with areducing agent; or

f. a compound of general Formula IX ##SPC9##

wherein R₁, R₃ and Q have the values given for Formula I, is treatedwith an alkylating agent; and

optionally, in a thus-obtained compound of Formula I, and R₁ group isconverted into another R₁ group by treatment with an esterifying,interesterifying or solvolyzing agent and/or a thus-produced oxocompound is converted into the corresponding hydroxy compound bytreatment with a reducing agent or a thus-obtained hydroxy compound isconverted into the corrresponding oxo compound by treatment with anoxidizing agent and/or a thus-produced compound of Formula I isconverted, by treatment with an acid or base, into a physiologicallyacceptable acid addition or metal or ammonium salt thereof,respectively, and/or a compound of Formula I is liberated from a saltthereof with an acid or a base, by treatment with a base or with anacid, respectively.

In the above formulae, R₁ and R₂ each preferably are H. When R₁ and R₅,which can be alike or different, are lower-alkyl, they preferably aremethyl or ethyl, but can also be n-propyl, isopropyl, n-butyl, isobutyl,sec.-butyl or tert.-butyl. Hereinbelow, A stands for alkyl of 1 to 4carbon atoms.

X and Z₁ are preferably Cl or Br but can also be, in addition to freeOHH and I, for example, alkylsulfonyloxy, especially of 1-6 carbon atoms(e.g., methanesulfonyloxy), arylsulfonyloxy, particularly of 6-10 carbonatoms and 1-2 separate or fused rings (e.g., benzenesulfonyloxy,p-toluenesulfonyloxy, 1- or 2-naphthalensulfonyloxy), or acyloxy,especially alkanoyloxy of 1-7 carbon atoms (e.g., acetoxy) andcarbocycloaroyloxy (e.g., benzoyloxy); Z₁ can also be NH₂ or anetherified OH-group of 1-7 carbon atoms, preferably methoxy orbenzyloxy.

The production methods described hereinbelow in greater detail areexecuted in accordance with the conditions described in the literaturefor these reactions and suitable therefor.

Preferably, compounds of Formula I are obtained by reacting a phenol IIwith an acetic acid derivative III. The penols III are, in part, known.They can be prepared according to methods known per se from theliterature, for example by splitting the methyl ethers thereof(compounds otherwise corresponding to those of Formula II, but having anOCH₃ in place of OH) with HBr. For the most part, compounds of FormulaIII are known. They can likewise be produced according to conventionalmethods.

A phenol II can first be converted into a salt, particularly into ametal salt, e.g., an alkali metal salt, preferably a Li, Na or K salt.For purposes of salt formation, the phenol can be reacted with a reagentforming salts (e.g., an alkali metal, such as Na, an alkali metalhydride or amide, such as LiH, NaH, NaNH₂ or KNH₂), a lower alkali metalalcoholate, such as lithium, sodium or potassium methylate, ethylate ortert.-butylate, an organometallic compound, such as butyllithium,phenyllithium or phenylsodium, a metal hydroxide, carbonate orbicarbonate, such as lithium, sodium, potassium or calcium hydroxide,carbonate or bicarbonate. The salt of II is advantageously produced inthe presence of a solvent, e.g., a hydrocarbon, such as hexane, benzene,toluene, or xylene; an ether, such as diethyl ether, diisopropyl ether,tetrahydrofuran (THF), dioxane or diethylene glycol diemthyl ether; andamide, such as dimethylformamide (DMF), or hexamethylphosphoric triamide(HMPA); an alcohol, such as methanol or ethanol; a ketone, such asacetone or butanone; or also a solvent mixture. The phenol II orpreferably a salt thereof is reacted with compound III, preferably inthe presence of a diluent, e.g., the solvent used for the preparation ofthe salt, but which can be replaced by another solvent or diluted withsuch a solvent. The reaction is normally conducted at temperatures ofbetween -20° and 150°, preferably between 20° and 120°, particularlyadvantageously at the boiling temperature of the solvent. The reactioncan be accomplished under an inert gas, e.g., nitrogen. The phenolatecan also be formed in situ, in which case the phenol II and compound IIIare allowed to react with each other in the presence of the salt-formingreagent.

A particularly preferred method resides in refluxing the compounds IIand III (X = Cl or Br, R₁ = CH₃ or C₂ H₅) for several hours togetherwith an alcoholic (e.g., ethanolic) sodium alcoholate solution.

It is also possible to react a free phenol II with a hydroxy acidderivative of Formula III (X = OH), preferably in the presence of acondensation agent. Suitable condensation agents are, for example,acidic dehydration catalysts, e.g., mineral acids, such as sulfuric acidor phosphoric acid, and also p-toluenesulfonyl chloride, arsenic acid,boric acid, NaHSO₄ or KHSO₄, and also diaryl carbonates (e.g., diphenylcarbonate), dialkyl carbonates (e.g., dimethyl or diethyl carbonate), orcarbodiimides (e.g., dicyclohexylcarbodiimide). If an acid is used asthe condensation agent, the reaction is suitably conducted in an excessof this acid without adding another solvent at temperatures of betweenabout 0° and about 100°, preferably between 50° and 60°. However, it isalso possible to add a diluent, e.g., benzene, toluene or dioxane. Witha carbonic acid ester, the process is preferably conducted at anelevated temperature, suitably between about 100° and about 210°,particularly between 180° and 200°. Optionally, an interesterificationcatalyst, e.g., sodium carbonate, potassium carbonate or sodiummethylate, can also be added.

To produce a compound of Formula I, the phenol II can also be reactedwith a holoform (preferably chloroform or bromoform) and a carbonlycompound of the formula R₂ --CO-R₃ (preferably acetone) in the presenceof a condensation agent. Especially suitable as a condensation agent isa strong base, such as an alkali metal hydroxide, e.g., NaOH or KOH,which is preferably used in the solid form. This reaction isadvantageously effected in the presence of a diluent, e.g., in thepresence of an excess of acetone and/or chloroform. Suitably, thereaction is conducted at temperatures of between about 20° and about150° preferably at the boiling temperature of the reaction mixture. Thereaction times range generally between 3 and 40 hours.

Compounds of Formula I can also be obtained by the cyclization ofcompounds of Formula IV according to methods known in the literature.

The starting compounds of Formula IV are obtainable according to methodsknown from the literature. Thus, the amino compounds IV[Z = Z₁ -Y₁-NH-(A₁)_(n) -] can be prepared, for example, by reacting a compound ofthe formula Z₁ -Y₁ -Z₁ (wherein Y₁ and Z₁ have the aforedescribedmeanings, e.g., 1,5-dichloro-, 1,5-dibromo-, or 1,5-diiodopentane,o-xylylene chloride, o-xylylene bromide, o-xylylene iodide, phthalylalcohol and the reactive esters thereof, e.g., the bismethansulfonate orbis-p-toluenesulfonate, o-xylylene diamine, phthalan [=isocoumaran],isoindoline) with a compound of the formula H₂ N-(A₁)_(n) -(p-C₆H₄)-O-CR₂ R₃ COOR₁ (Formula X, wherein R₁, R₂, R₃, A₁ and n have theabove-indicated meanings).

Suitable solvents for the cyclization of these starting materials [IV, Z= Z₁ -Y₁ -NH-(A₁)_(n) -] are, for example, water; lower aliphaticalcohols, e.g., methanol, ethanol, isopropanol, n-butanol; glycols,e.g., ethylene glycol; ethers, e.g., diethyl or diisopropyl ether, THF,dioxane; aliphatic or aromatic hydrocarbons, e.g., hexane, benzene,toluene, xylene; halogentated hydrocarbons, e.g., chloroform,chlorobenzene; nitriles, e.g., acetonitrile; amides, e.g., DMF,dimethylacetamide; sulfoxides, e.g., dimethyl sulfoxide; and mixtures ofthese solvents. Normally, the cyclization is carried out at temperaturesof between about 0° and about 300°, preferably between room temperatureand the boiling temperature of the solvent employed. The selection ofthe catalyst is dependent on the type of the compound HZ₁ to be splitoff. When Z₁ is halogen, inorganic or organic bases are preferred, e.g.,alkali metal or alkaline earth metal hydroxides, carbonates oralcoholates, tertiary bases, e.g., triethylamine, pyridine, picolines orquinoline. When Z₁ is OH, alkoxy, acyloxy, alkyl- or arysulfonyloxy,however, acidic catalysts are advantageous, e.g., inorganic or organicacids, for example, sulfuric acid, polyphosphoric acid, hydropbromicacid, hydrochloric acid, formic, acetic, propionic, or p-toluenesulfonicacid, which in an excess can likewise serve as the solvent. Compoundswherein Z₁ is NH₂ split off ammonia during heating, e.g., duringmelting, thus producing the desired compounds of Formula I.

In a preferred mode of operation, the compounds of Formula IV [Z = Z₁-Y₁ -NH-(A₁)_(n) -] are not isolated but are produced in the nascentstate in the presence or absence of an additional solvent and cyclizeddirectly in the thus-obtained reaction mixture.

The reaction of a compound of the formula Br-Y₁ -Br with an amine ofFormula X is especially advantageous in a boiling alcohol in thepresence of potassium carbonate, thus obtaining, as an intermediateproduct, a compound of Formula IV (Z₁ = Br) which is cyclized situ.Under these conditions, the reaction is terminated after about 1-12hours. If desired, unreacted primary (Formula X) and/or secondary(Formula IV) amino compounds can be converted, prior to furtherprocessing, into compounds which are not basic by means of acylation,e.g., by treatment with acetic anhydride.

The compounds IV [Z = Z₂ -CH₂ CH₂ -N(C₆ H₅)-] can be obtained, forexample, from the corresponding diphenylamines of the formula C₆ H₅NH-(p--C₆ H₄)-O--CR₂ R₃ -COOR₁ with β-propiolactone or derivatives ofacrylic acid, as well as by an optionally subsequently conductedfunctional modification of the Z₂ group. Acids of Formula IV (Z₂ = COOH)can be cyclized in accordance with methods known in the literature witha dehydration agent, e.g., ZnCl₂, polyphosphoric acid, or SnCl₄. Alsofunctional derivatives of these acids, e.g., the halogenides thereof,especially the chlorides thereof and also the anhydrides, nitriles oresters thereof, for example, can be cyclized, preferably in the presenceof an acidic catalyst, such as AlCl₃, H₂ SO₄ or BF₃. The cyclization isnormally accomplished at temperatures of between about 0° and about250°, preferably between 20° and 200 °,especially between 75° and 150°.The presence of an additional solvent, e.g., acetic acid, aceticanhydride or nitrobenzene, can be advantageous, but is not required,especially if the cyclizing agent serves simultaneously as the solvent.

Compound of Formula IV (Z = C₆ H₅ -Y₂ -CH₂ CH₂ -CHX-, obtainable, forexample, by Friedel-Crafts acylation of compounds of Formula VII (X₂ =H) with 3-chloropropionyl chloride, subsequent reaction with sodiumphenolate, sodium phenyl mercaptide, or diphenylamine and reduction ofthe keto group) can be cyclized by intramolecular Friedel-Craftsalkylation, suitably in the presence of an acidic catalyst, e.g., HF,HCl, HBr, AlCl₃, FeCl₃ or SnCl₄ and in the presence of an inert solvent,e.g., carbon disulfide, nitrobenzene or chlorobenzene, or also in thepresence of an excess of the cyclizing agent, e.g., concentrated aqueousHBr solution at temperatures of between 0° and 200°, preferably between20° and 150°.

Compounds of Formula IV [Z = HY₂ -(o-C₆ H₄)-CH(CH₂ CH₂ X)-, obtainableby condensation of a 2-Y₂ H-4'-hydroxybenzophenone with malonic acid,stepwise reduction to the saturated alcohol, and reaction with compoundsof Formula III] are suitably cyclized in the presence of an alkalinecatalyst, e.g., alkali metal alcoholates, such as sodium ethylate, oralkali metal hydrides, such as NaH in inert solvents, such as methanol,ethanol or DMF at temperatures of between about 0° and about 120°,preferably between 20° and 80°.

Compounds of Formula I are also obtainable in accordance with methodsdescribed in the literature by solvolysis (preferably hydrolysis) ofcompounds of Formula V wherein W is one of the following groups (whereinthe R₆ and R₇ groups which are to be split off can be an organic group,but especially are alkyl of 1-4 carbon atoms, preferably methyl orethyl, which can be alike or different but also collectively can betetramethylene or pentamethylene, optionally interrupted by O): CHal₃(wherein Hal is Cl, Br, or I); COHal; COOR₈ (wherein R₈ is a groupdifferent from R₁, particularly alkyl of 5-12 carbon atoms or asubstituted alkyl residue which, however, differs from A); C(OR₆)₃ ;COOAcyl [wherein Acyl is the acyl radical of a carboxylic acid of up to25 carbon atoms, preferably an acid of Formula I (R₁ = H)]; CN; CONH₂ ;COHNR₆ ; CONR₆ R₇ ; CONHOH: C(OH) =NOH; CONHNH₂ ; CON₃ ; C(OR₆)=NH;C(NH₂)=NNH.sub. 2 ; C(NHNH₂)=NH; CSOH: COSH: CSOR₆ ; CSNH₂ ; CSNHR₆ ; orCSNR₆ R₇. Preferably, W is nitrile or acid amide. Compounds of Formula Vare obtainable, for example, by the reaction of phenols of Formula IIwith acetic acid derivatives of the formula X-CR₂ R₃ -W.

Compounds of Formula V can be solvolyzed in an acidic or alkaline mediumat temperatures of between about -20° and 300°, preferably at theboiling temperature of the selected solvent. Suitable acidic catalystsare, for example, hydrochloric, sulfuric, phosphoric, or hydrobromidacid. Examples of suitable basis catalysts are sodium, potassium, orcalcium hydroxide, sodium or ptoassium carbonate. Preferred solvents arewater; lower alcohols, such as methanol, ethanol; ethers, such as THF,dioxane; amides, such as DMF; nitriles, such as acetonitrile; sulfones,such as tetramethylenesulfone; and mixtures thereof, especially thewater-containing mixtures. The preferred hydrolysis of nitriles (V, W =CN) and acid amides (V, W = CONH₂, CONHR₆ or CONR₆ R₇) is advantageouslyconducted in an acidic medium (e.g., with acetic acid/hydrochloric acid)or in an alkaline medium (e.g., with ethanolic KOH).

Compounds of Formula I can also be produced according to methods knownfrom the literature by the reaction of compounds of Formula VI withcompounds of Formula VII. Starting compounds VI and VII are known andare obtained in accordance with methods described in the literature.

More specifically, it is possible, for example, to react N-halomines ofFormula VI (X₁ = Cl or Br), such asN-chloro-1,2,3,4-tetrahydro-4-quinolone,N-chloro-1,2,3,4-tetrahydro-4-hydroxyquinoline, or the correspondingN-bromo compounds or the corresponding reactive derivatives of N-hydroxycompounds, e.g., N-hydroxy-1,2,3,4-tetrahydro-4-quinolone-O-sulfonicacid, with carboxylic acid derivatives of Formula VII (X₂ = H), e.g.,phenoxyacetic acid, α-phenoxyisobutyric acid, orα-p-chlorophenyl-α-phenoxyacetic acid, or the esters of these acids,preferably in the presence of a catalyst, e.g., metallic salts, such asiron(II) sulfate, AlCl₃, BF₃ or ZnCl₂, in an inert solvent, such as CS₂,nitrobenzene, 1,2-dichloroethane, or, with the use of FeSO₄, inconcentrated or aqueous sulfuric acid. In this mode of operation, thereaction temperatures are advantageously between about -20° and about+60°, preferably between 0° and 40°.

The free amines of Formula VI (X₁ = H), e.g.,1,2,3,4-tetrahydro-4-quinolone and 1,2,3,4-tetrahydro-4-hyroxyquinoline,can be reacted with amino compounds of Formula VII (X₂ = NH₂), e.g.,α-p-aminophenoxyacetic acid, α-p-aminophenoxyisobutyric acid, andα-p-aminophenoxy-α-p-chlorophenylacetic acid or the esters thereof,preferably under pressure and with an excess of the amine VI as thesolvent, and/or in the presence of an additional inert solvent, as wellas an acidic catalyst, such as HCl or p-toluenesulfonic acid orFriedel-Crafts catalyst, catalyst, such as AlCl₃ at temperatures ofbetween about 50° and about 300°, preferably between 150° and 250°.

Metal derivatives, especially the Na-derivatives, of the aforementionedamines of Formula VI (X₁ = H), can be reacted with halo or sulfonic acidderivatives of Formula VII (X₂ = Cl, Br, I or So₃ M), e.g.,α-p-bromophenoxyacetic acid, α-p-bromophenoxyisobutyric acid,α-p-bromophenoxy-α-p-chlorophenylacetic acid, α-p-sulfophenoxyaceticacid, and the salts and/or esters thereof, preferably in the presence ofan excess of the base Vi as the solvent and/or in the presence of anadditional inert solvent or suspension agent, such as benzene, dioxane,DMF, or HMPA, at temperatures of between 50° and 200°, optionally underpressure and/or an inert gas atmosphere. The metal derivatives of theamines VI can also be produced in situ, e.g., with NaH or NaNH₂.

Compounds of Formula I can also be obtained according to methodsdescribed in the literature by reduction of the corresponding3-chromene-, 3-thiochromene- and 1,2-dihyrdoquinoline derivatives ofFormula VIII.

The reduction of these starting substances can suitably be accomplishedby catalytic hydrogenation or by chemical processes. The startingcompounds can be treated, for example, in the presence of a catalyst,with hydrogen under pressures of between 1 and about 200 atmospheres andat temperatures of betwen about -80° and 200°, preferably between 20°and 100°. The hydrogenation is advantageously effected in the presenceof an inert solvent, e.g., a lower alcohol, such as methanol, ethanol orisopropanol or an ether, such as dioxane. For purposes of hydrogenation,the free compounds of Formula VIII can be utilized, or the correspondingsalts, for example the sodium salts of the carboxylic acids VIII (R₁ =H). Examples of suitable catalysts are the noble metal, nickel andcobalt catalysts. The noble metal catalysts can be present on a support(e.g., on carbon, calcium carbonate or strontium carbonate), as oxidecatalysts, or as finely divided metallic catalysts. Platinum orpalladium is preferably utilized.

Reduction of the compounds VIII can also be accomplished by chemicalmethods, e.g., with nascent hydrogen, which can be produced, forexample, from sodium or sodium amalgam in an alcoholic solution. In thisreduction method, temperatures of between about 0° and about 150° areemployed.

The starting compounds of Formula VIII can be obtained, for instance, byreacting 4-chromanone or 4-thiochromanone or1-phenyl-1,2,3,4-tetrahydro-4-quinolinone with compounds otherwisecorresponding to Formula VII but having a metal M in place of X₂, e.g.,p-(2-carboxy-2-propoxy)-phenyllithium. During this reaction, theocrresponding carbinols are first produced, which can, however, bedehydrated to the compounds of Formula VIII extremely readily. In fact,these latter compounds are normally formed during the working-upoperation.

the phenoxyacetic acid derivatives I (R₄ = Q) are also obtained by thealkylation of the acid derivatives IX. These are, in part, known. Theycan be produced, for example, by reacting the phenols II with compoundsof the formula Z-CHR₃ -COOR₁ under the conditions set forth above forthe reaction of compounds II with compounds III.

Suitable for the alkylation of IX are, for example, the followingalkylation agents: alkyl halides, such as methyl chloride, bromide,iodide, ethyl chloride, bromide, iodide, and the aryl sulfonates andalkyl sulfates, e.g., mehtyl p-toluenesulfonate and dimethyl sulfate.Prior to the alkylation, the compounds IX are suitably converted into ametal derivative thereof, e.g., by reaction with an alcoholate, such assodium ethylate or potassium tert. -butylate, a metal hydride, such assodium hydride, a metal ammide, such as sodium amide or lithiumdiisopropylamide, an organometallic compound, such as n-butyllithium, ora metal, such as sodium (e.g., in liquid ammonia). This conversion takesplace suitably in an inert solvent, e.g., an alcohol, such as methanol,ethanol or tert. -butanol, an ether, such as diethyl ether, an amide,such as DMF or HMPA or a hydrocarbon, such as benzene, and in mixturesof these solvents. The reaction with the alkylating agent isadvantageously effected subsequently in the same reaction mixture. Thereaction temperatures range normally between about -20° and +120°,preferably between about 0° and 80°, and the reaction times rangebetween about 1 hour and 48 hours.

If desired, the R₁ group in a thus-obtained compound of Formula I can beconverted into another R₁ group in accordance with methods disclosed inthe literature by esterification, transesterification or solvolysis.

For example, it is possible to esterify a thus-produced acid of FormulaI (R₁ = H) with an alcohol of the formula A-OH, suitably in the presenceof an inorganic or organic acid, such as HCl, HBr, HI, H₂ PO₄,trifluoroacetic acid, benzensulfonic acid, or p-toluenesulfonic acid orin the presence of an acidic ion exchanger, optionally in the presenceof an inert solvent, such as benzene, toluene or xylene, at temperaturesof between about 0° and preferably the boiling temperature. The alcoholis preferably used in large molar excess. The esters can also beobtained by chemically adding the carboxylic acids I (R₁ = H) to olefins(e.g., isobutylene) or by reacting the carboxylic acids withdiazoalkanes, e.g., diazomethane. Furthermore, the esters can beprepared by reacting metallic salts of the acids I (R₁ = H), preferablythe alkali metal, lead or silver salts, with halogenides of the formulaA-Hal or with corresponding chlorosulfites of the formula A-OSOCl, andthe thus-produced adducts are thereafter thermally decomposed. Theesterification can also be conducted in several stages. For example, itis possible first to produce from the acid I (R₁ = H) the correspondingacid halogenide, e.g., the acid chloride, and react the latter with thealcohol A-OH, optionally in the presence of an acidic or basic catalyst.

Furthermore, the desired esters of Formula I (R₁ = A) can be obtained bytransesterification, especially by reacting other esters with an excessof the respective alcohol or by reacting the carboxylic acids I (R₁ = H)with any desired other ester of the respective alcohol (preferablyalkanoates, wherein the alkanolyl residue has up to 4 carbon atoms),especially in the presence of basic or acidic catalysts, e.g., sodiumethylate or sulfuric acid, and at temperatures of between about 0° andpreferably the boiling temperature.

it is also possible, in a thus-obtained compound of Formula I, toconvert the R₁ group by treatment with solvolyzing agents, into anotherR₁ group, especially saponifying a thus-produced ester of Formula I (R₁= ) to the corresponding acid I (R₁ = H). The solvolysis and/orsaponification can be accomplished in accordance with one of the methodsindicated above for the solvolysis of the compounds of Formula V.Preferably, the esters are saponified by treatment with alcoholic alkalisolutions, e.g., ethanolic potassium hydroxide, at temperatures ofbetween about 20° and 120°, preferably at the boiling point of thesolution.

Oxo compounds obtained in this manner can be reduced to thecorresponding hydroxy compounds by treatment with a reducing agent,preferably a complex metal hydride, in accordance with methods known perse from the literature. Suitable reducing agents are sodium borohydridein methanol or ethanol, optionally in the presence of AlCl₃ or LiBr. Thereaction is effected in an inert solvent, e.g., a lower alcohol, ether,THF or ethylene glycol dimethyl ether. The reaction temperatures rangebetween about 0° and 120°. Preferably, the process is conducted at roomtemperature, but the reaction can also be terminated by boiling thereaction mixture.

Conversely, a thus-obtained hydroxy compound can be converted into thecorresponding oxo compound by treatment with an oxidizing agent. A largenumber of methods known from the literature can be utilized for thispurpose. Preferably, the oxidation is accomplished with dimethylsulfoxide, together with a dehydration agent, e.g.,dicyclohexylcarbodiimide, or with CrO₃ in an organic solvent, forexample, dimethylformamide or acetic acid.

A basic compound of Formula I can be converted into an acid additionsalt thereof with an acid. Suitable are acids forming pharmaceuticallyacceptable, i.e., physiologically acceptable, salts. Thus, advantageousare organic and inorganic acids, e.g., aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic orsulfonic acids, such as formic acid, acetic acid, propionic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid,phenylpropionic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonicacid, naphthalene-mono- and -disulfonic acids, sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid orphosphoric acids, such as orthophosphoric acid.

Similarly, acids of Formula I (R₁ = H) can be converted into one of thephysiologically acceptable metal and/or ammonium salts thereof byreaction with a base. Examples of suitable salts are the sodium,potassium, magnesium, calcium, ammonium salts and substituted ammoniumsalts, such as, for example, the dimethyl-, diethyl- anddiisopropylammonium, monoethanol-, diethanol-, and triethanolammonium,cyclohexylammonium, dicyclohexylammonium and dibenzylethylenediammoniumsalts.

Conversely, compounds of Formula I can be liberated from the acidaddition salts thereof by treatment with strong bases and/or from themetal and ammonium salts thereof by treatment with acids.

The compounds of Formula I can contain one or more centers of asymmetryand are ordinarily present in the racemic form. The racemates can beseparated into their optical antipodes with the aid of conventionalmethods as indicated in the literature. Furthermore, it is, of course,possible to obtain optically active compounds in accordance with theabove-described methods, by the use of starting substances which arealready optically active.

The compounds of Formula I possess with good compatibility, valuablepharmacological properties, including cholestesterol-level-lowering, aswell as triglyceride-level-lowering, uric-acid-level-lowering andliver-enzyme-inducing activity. This can be demonstrated in accordancewith methods known for this purpose. See, e.g., Levine et al.,"Automation in Analytical Chemistry," Technicon Symposium, 1967, Mediad,New York, pp. 25-28; (lowering of cholesterol level); and Noble andCampbell, Clin. Chem., Vol. 16, 1970, pp. 166-170; (lowering oftriglyceride level), in each case in the rat serum.

The compounds of Formula I and the physiologically acceptable salts canbe used as drugs and also as intermediates for the production of othermedicines.

The compounds of Formula I and/or optionally the physiologicallyacceptable salts thereof can be employed as drugs in the human orveterinary medicine in admixture with a pharmaceutically acceptablecarrier, viz., solid, liquid and/or semiliquid excipients and, ifdesired, in combination with other effective agents. Suitable vehiclesare those organic or inorganic substances suitable for parenteral,enteral or topical application and which do not react with the novelcompounds, such as, for example, water, vegetable oils, benzyl alcohols,polyethylene glycols, gelatin, lactose, amylose, magnesium stearate,talc, vaseline, cholesterol. Suitable for parenteral application are, inparticular, solutions, preferably oily or aqueous solutions, as well assuspensions, emulsions or implants. For enteral application, suitableare tablets, dragees, capsules, syrups, elixirs or suppositories, andfor topical application ointments, creams or powders. Theabove-indicated preparations can optionally be sterilized or can containauxiliary agents, such as lubricants, preservatives, stabilizers orwetting agents, emulsifiers, salts to influence the osmotic pressure,buffer substances, coloring, flavoring and/or aromatic substances.

The compounds are preferably administered in doses of between 10 to 1000mg. per dosage unit. Oral administration is preferred, particularly indoses of between 50 and 500 mg. per dosage unit.

In test animals, particularly in rats, the activities occurred whendoses of about 10 to 100 mg./kg. were applied. Other suitable testanimals are, f.e., mice, rabbits, guinea pigs, dogs, monkeys and pigs.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever.

The temperatures set forth herein are in degrees Celsius.

PREPARATION

a. 23 g. of 4-hydroxydiphenylamine are heated to 130°. After addition of0.56 g of zinc chloride, the mixture is heated to 150° and 9.4 g. ofβ-propiolactone are added dropwise. The mixture is stirred for 15minutes, cooled and taken up in ethylacetate. By extraction with dilutesodium hydroxide solution and acidification3-[N-phenyl-N-(4-hydroxyphenyl)-amino]propionic acid of m.p. 173°-175°is obtained.

b. A mixture of 30 g. of this acid, 800 ml of acetic acid and 55 ml. ofacetic anhydride is warmed to 90°. A solution of 16 g. of zinc chloridein 165 ml. of acetic anhydride is added, the resulting mixture is boiledfor 10 minutes, cooled, and poured into water. After extraction withether and usual working up,1-(4-acetoxyphenyl)-4-oxo-1,2,3,4,-tetrahydroquinoline (A) of m.p.130°-132° is obtained (from ethanol).

c. Conventional alkaline saponification of compound A [method seeExample 1b), below] yields1-p-hydroxyphenyl-1,2,3,4-tetrahydro-4-quinolone; m.p. 190°-192°.

d. Conventional sodium borohydride reduction of compound A [method seeExample 2c), below] yields1-p-hydroxyphenyl-4-hydroxy-1,2,3,4-tetrahydro-quinoline.

e. Conventional Wolff-Kishner reduction of compound A [method seeOrganic Reactions IV, 378 (1948)] yields1-p-hydroxyphenyl-1,2,3,4-tetrahydro-quinoline, m.p. 112°-114°.

EXAMPLE 1

a. 2.3 g. of sodium is dissolved in 100 ml. of absolute ethanol; 17.7 g.of4-piperidinophenol is introduced into the solution, and then 24.3 g.of ethyl α-bromophenylacetate is added dropwise thereto and themixturerefluxed for 10 hours. The reaction mixture is then evaporated,the residuemixed with water, and the aqueous solution extracted withethyl acetate. The ethyl acetate solution is washed twice with diluteKOH and twice with water, then dried, and the solvent is evaporated,thus obtaining the ethylester of α-phenyl-α-4-piperidinophenoxyaceticacid; hydrochloride, m.p. 149°-151°.

Analogously, the following compounds are produced with ethylα-bromophenylacetate from the corresponding phenols of Formula II:

ethyl ester of α-phenyl-α-4-isoindolinophenoxyacetic acid, m.p.132°

ethyl ester of α-phenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,m.p. 96°-98°

ethyl ester ofα-phenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

ethyl ester ofα-phenyl-α-4-(1-methyl-1,2,3,4,-tetrahydro-4-quinolyl)-phenoxyaceticacid, oil, n_(D) ²⁰ 1.5950

ethyl ester of α-phenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid,m.p. 126°-128°

ethyl ester of α-phenyl-α-4-(4-piperidinophenoxy)-phenoxyaceticacid

ethyl ester of α-phenyl-α-4-(1-pyrryl)-phenoxyacetic acid.

Analogously, the following products are obtained with the ethyl ester of2-chloropropionic acid, the ethyl ester ofα-bromo-α-(o-chlorophenyl)-acetic aacid, the ethyl ester ofα-bromo-α-(m-chlorophenyl)-acetic acid, and the ethyl ester ofα-bromo-α-(p-chlorophenyl)-acetic acid:

the ethyl ester of each of the following acids, respectively:

α-4-piperidinophenoxypropionic acid

α-4-isoindolinophenoxypropionic acid

α-4-(1,2,3,4-tetrahydroquino)-phenoxypropionic acid

α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid

α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid

α-4-(4-piperidinophenyl)-phenoxypropionic acid

α-4-(4-piperidinophenoxy)-phenoxypropionic acid

α-4-(1-pyrryl)-phenoxypropionic acid

α-o-chlorophenyl-α-4-piperidinophenoxyacetic acid

α-o-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-o-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid

α-o-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid

α-m-chlorophenyl-α-4-piperidinophenoxyacetic acid; hydrochloride, m.p.149°-151°

α-m-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-m-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)phenoxyaceticacid

α-m-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid, m.p.96°-97°

α-m-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid

α-p-chlorophenyl-α-4-piperidinophenoxyacetic acid

α-p-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid,oil, n_(D) ²⁰ 1.6129

α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-p-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)phenoxyaceticacid

α-p-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid, m.p. 122°

α-p-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-p-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid, m.p. 109°.

b. 3.39 g. of the ethyl ester of α-phenyl-α-4-piperidinophenoxyaceticacid is refluxed for 2 hours with 3 g. of KOH in 30 ml. of ethanol. Themixture is then evaporated, mixed with water, extracted with ether, andhydrochloric acid is added to pH 4. The thus-obtainedα-phenyl-α-4-piperidinophenoxyacetic acid is filtered.

Analogously, the following compounds are produced by saponification ofthe corresponding ethyl esters:

α-phenyl-α-4-isoindolinophenoxyacetic acid

α-phenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid;diisoproylamine salt, m.p. 169°-171°

α-phenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid;cyclohexylamine salt, m.p. 241°-243°

α-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid; diisopropylamine salt, m.p. 165°-168°

α-phenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid

α-phenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-phenyl-α-4-(1-pyrryl)-phenoxyacetic acid

α-4-piperidinophenoxypropionic acid

α-4-isoindolinophenoxypropionic acid

α -4-(1,2,3,4-tetrahydroquinolino)-phenoypropionic acid

α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid

α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid;cyclohexylamine salt, m.p. 203°-205°

α-4-(4-piperidinophenyl)-phenoxypropionic acid, m.p. 215°

α-4-(4-piperidinophenoxy)-phenoxypropionic acid, m.p. 160°-162°

α-4-(1-pyrryl)-phenoxypropionic acid

α-o-chlorophenyl-α-4-piperidinophenoxyacetic acid

α-o-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-o-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid

α-o-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-o-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid

α-m-chlorophenyl-α-4-piperidinophenoxyacetic acid, m.p. 185°-190°

α-m-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-m-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)phenoxyaceticacid

α-m-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid

α-m-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid

α-p-chlorophenyl-α-4-piperidinophenoxyacetic acid, m.p. 173°-175°

α-p-chlorophenyl-α-4-isoindolinophenoxyacetic acid

α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid;diisopropylamine salt, m.p. 155°-158°

α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-p-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid; diisopropylamine salt, m.p. 174°-181°

α-p-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid

α-p-chlorophenyl-α-4-(4-piperidinophenoxy)-phenoxyacetic acid;cyclohexylamine salt, m.p. 240°-242°

α-p-chlorophenyl-α-4-(1-pyrryl)-phenoxyacetic acid.

EXAMPLE 2

a. Analogously to Example 1(a), the methyl ester of2-methyl-2-p(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,m.p. 76°-78° (from hexane), is obtained from1-p-hydroxyphenyl-1,2,3,4-tetrahydro-4-quinolone and the methyl ester ofα-bromoisobutyric acid in absolute methanol in the presence of sodiummethylate (48 hours).

In an analogous manner, the following compounds are obtained from1-p-hydroxyphenyl-1,2,3,4-tetrahydro-4-quinolone and1-p-hydroxyphenyl-4-hydroxy-1,2,3,4-tetrahydroquinoline with the methyland ethyl esters, respectively, of bromoacetic acid, α-bromopropionicacid, α-bromobutyric acid, α-bromoisobutyric acid, α-bromocaproic acid,α-bromophenylacetic acid, α-bromo-α-o-chlorophenylaceticacid,α-bromo-α-m-chlorophenylacetic acid and α-bromo-α-p-chlorophenylaceticacid:

methyl ester of α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxy-aceticacid,

ethyl ester of α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,

the methyl ester and the ethyl ester ofα-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxybutyric acid,

the ethyl ester of2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,

the methyl ester and the ethyl ester ofα-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxycaproic acid,

the methyl ester and the ethyl ester ofα-phenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

methyl ester of2-phenyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,

the ethyl ester of2-phenyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,oil, n_(D) ²⁰ 1.5898,

the methyl ester and the ethyl ester ofα-o-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-m-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid,

the methyl ester and the ethyl ester ofα-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,

the methyl ester and the ethyl ester ofα-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxybutyric acid,

the methyl ester and the ethyl ester of2-methyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid,

the methyl ester and the ethyl ester ofα-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxycaproic acid,

the methyl ester and the ethyl ester ofα-phenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid,

the methyl ester and the ethyl ester of 2-phenyl-2-(4hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,

the methyl ester and the ethyl ester ofα-o-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-m-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid,

the methyl ester and the ethyl ester ofα-p-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid.

b. Analogously to Example 1(b),2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acidis obtained from the methyl ester of2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)1phenoxypropionic acidwith KOH in methanol (4hours of refluxing).

Analogously, the following final products are obtained by thesaponification of the corresponding methyl and ethyl esters,respectively;

α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid;cyclohexylamine salt, m.p. 180°

α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxybutyric acid

α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxycaproic acid

α-phenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid;cyclohexylamine salt, m.p. 170°

2-phenyl12-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid;cyclohexylamine salt, m.p. 178°-180°

α-o-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid

α-m-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid

α-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid, m.p. 180°-185°

α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid

α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxybutyric acid

2-methyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid

α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxycaproic acid

α-phenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid

2-phenyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid

α-o-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid

α-m-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid

α-p-chlorophenyl-α-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid.

c. A solution of 3.39 g. of the methyl ester of2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acidin 40 ml. of methanol is mixed under agitation with 0.4 g. of NaBH₄ andthen stirred for 1 hour 25°. The mixture is then poured intowater,extracted with ether, dried, evaporated, and the product thusobtained is the methyl ester of2-methyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid.

d. A mixture of 3.41 g. of the methyl ester of2-methyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid, 3 g. of dicyclohexylcarbodiimide, 0.8 ml. of pyridine, 0.4 ml. oftrifluoroacetic acid, 25 ml. of dimethyl sulfoxide, and 25 ml. ofbenzene is allowed to stand overnight at 25°. After adding etherthereto, the mixture is filtered, the filtrate diluted with water, andworked up asusual, thus producing the methyl ester of2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,m.p. 76°-78°.

EXAMPLE 3

a. 2.3 g. of sodium is dissolved in 170 ml. of absolute isopropanol, and22.6 g. of 4-p-hydroxyphenylchromane (obtainable by reacting 4-chromanolwith phenol in the presence of AlCl₃) is introduced into thereactionmixture; 15 g. of the ethyl ester of 2-chloroisobutyric acid isadded dropwise and the mixture refluxed for 20 hours. After working themixture up as usual, the oily ethyl ester of2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid is obtained.

Analogously, the following compounds are produced from4-p-hydroxyphenylchromane, 4-p-hydroxyphenylthiochromane (obtainablefrom 4-hydroxythiochromane) and1-phenyl-4-(p-hydroxyphenyl)-1,2,3,4-tetrahydroquinoline (obtainablefrom 1-phenyl-1,2,3,4-tetrahydro-4-hydroxyquinoline), respectively:

the methyl ester and the ethyl ester of2-p-(4-chromanyl)-phenoxypropionic acid,

the methyl ester of 2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid,

the methyl ester and the ethyl ester of α-phenyl-α-p-(4-chromanyl)--chromanyl)-phenoxyacetic acid,

the methyl ester and the ethyl ester ofα-o-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid,

the methyl ester and the ethyl ester ofα-m-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid,

the methyl ester and the ethyl ester ofα-p-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid,

the methyl ester and the ethyl ester of2-p-(4-thiochromanyl)-phenoxypropionic acid,

the methyl ester and the ethyl ester of2-methyl-2-p-(4-thiochromanyl)-phenoxypropionic acid,

the methyl ester and ethyl ester ofα-phenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid,

the methyl ester and ethyl ester ofα-o-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid,

the methyl ester and ethyl ester ofα-m-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid,

the methyl ester and ethyl ester ofα-p-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid,

the methyl ester and ethyl ester of2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid,

the methyl ester and ethyl ester of2-methyl-2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionicacid,

the methyl ester and ethyl ester ofα-phenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid,

the methyl ester and ethyl ester ofα-o-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid,

the methyl ester and ethyl ester ofα-m-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid,

the methyl ester and ethyl ester ofα-p-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid.

b. Analogously to Example 1(b),2-methyl-2-p-(4-chromanyl)-phenoxypropionicacid is obtained bysaponification of the ethyl ester of 2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid. Cyclohexylamine salt,m.p. 196°-198°.

In an analogous manner, the following products are obtained by thesaponification of the corresponding methyl and ethyl esters,respectively:

2-p-(4-chromanyl)-phenoxypropionic acid

α-phenyl-α-p-(4-chromanyl)-phenoxyacetic acid; cyclohexylamine salt,m.p. 215°-217°

α-o-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid

α-m-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid

α-p-chlorophenyl-α-p-(4-chromanyl)-phenoxyacetic acid

2-p-(4-thiochromanyl)-phenoxypropionic acid

2-methyl-2-p-(4-thiochromanyl)-phenoxypropionic acid; diisopropylaminesalt, m.p. 137°-1390°

α-phenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid; cyclohexylamine salt,m.p. 230°-241°

α-o-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid

α-m-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid

α-p-chlorophenyl-α-p-(4-thiochromanyl)-phenoxyacetic acid

2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionic acid

2-methyl-2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionicacid; diisopropylamine salt, m.p. 135°-138°

α-phenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid

α-o-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid

α-m-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid

α-p-chlorophenyl-α-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid.

EXAMPLE 4

a. Analogously to Example 1(a), the following compounds are obtainedfrom the corresponding phenols with 2-bromo-2-phenylpropionic acid ethylester:

ethyl ester of 2-phenyl-2-p-(4-chromanyl)-phenoxypropionic acid, oil,n_(D) ²⁰ 1.5832

ethyl ester of 2-phenyl-2-p-(4-thiochromanyl)-phenoxypropionic acid,oil, n_(D) ²⁰ 1.5969

ethyl ester of2-phenyl-2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionicacid.

b. Analogously to Example 1(b), the following products are obtained bysaponification of the aforementioned esters:

2-phenyl-2-p-(4-chromanyl)-phenoxypropionic acid; cyclohexylamine salt,m.p. 190°-193°

2-phenyl-2-p-(4-thiochromanyl)-phenoxypropionic acid; cyclohexylaminesalt,m.p. 187°-189°; sodium salt, m.p. 200°-202°

2-phenyl-2-p-(1-phenyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxypropionicacid.

EXAMPLE 5

22.5 g. of 4-(1,2,3,4-tetrahydroquinolino)-phenol is added to asuspension of 2.4 g. of NaH in 200 ml. of dimethylacetamide. The mixtureis stirred for one hour at room temperature, maintained at 90° for 20hours after the addition of 27.75 g. of the ethyl ester ofα-bromo-α-p-chlorophenylacetic acid, cooled, mixed with water,andextracted with ether. The ether solution is washed twice with 2N NaOHand evaporated after drying, thus obtaining the ethyl ester ofα-p-chlorophenyl -α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid.Free acid, diisopropylamine salt, m.p. 155°-158°.

EXAMPLE 6

A mixture of 2.26 g. of 4-p-hydroxyphenylchromane and 0.23 g. of sodiumin 50 ml. of xylene is refluxed for 3 hours. The mixture is allowed tocool to 20°; then, 2.57 g. of the ethyl ester of2-bromo-2-phenylpropionic acid in 10 ml. of xylene is added, thesuspension is agitated for 6 hours under boiling heat, cooled, andtreatedwith 2 ml. of ethanol. The inorganic precipitate is filtered off,the filtrate is evaporated, the residue is taken up in ether, thesolution is washed with NaHCO₃ solution and saturated NaCl solution,dried over MgSO₄, and evaporated, thus obtaining the ethyl ester of2-phenyl-2-p-(4-chromanyl)-phenoxypropionic acid, n_(D) ²⁰ 1.5832.

Analogously, with the use of the phenols set forth in Example 1, andreacting same with the propyl, isopropyl, n-butyl, isobutyl, sec.-butyland tert.-butyl esters, respectively, of α-bromopropionic acid,α-bromoisobutyric acid, α-bromophenylacetic acid,α-bromo-α-o-chlorophenylacetic acid, α-bromo-α-m-chlorophenylaceticacid, and α-bromo-α-p-chlorophenylacetic acid, one obtains thecorresponding esters of the acids indicated in Example 1(b), e.g. then-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, and tert.-butylestersof 2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid.

EXAMPLE 7

A solution of 27.75 g. of the ethyl ester ofα-bromo-α-p-chlorophenylacetic acid in 50 ml. of acetone is graduallyadded to an agitated mixture of 25.3 g. of4-(4-piperidinophenyl)-phenol, 13.8 g. of K₂ CO₃, and 80 ml. of acetone.The mixture is refluxed under stirring, filtered, and evaporated,thusproducing the ethyl ester ofα-p-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid, m.p. 122°.

EXAMPLE 8

15g. of sulfuric acid is added to a mixture of 25.3 g. of4-(4-piperidinophenyl)-phenol and 21.45 g. of the ethyl ester ofα-m-chlorophenylglycolic acid; the reaction mixture is agitated for 2hours at 50°-60°. After cooling, the mixture is combined with water,dilute NaOH is added to pH 8, and the aqueous phase is extracted withether. The mixture is then dried, evaporated, and the thus-obtainedproduct is the ethyl ester ofα-m-chlorophenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid, m.p.96°-97°.

EXAMPLE 9

a. 23.9 g. of 4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenol isdissolved in 200 ml. of acetone. Under agitation, 4g. of NaOH is addedto the mixture and thereafter, under agitation and boiling, 21.5 g. ofα-bromophenylacetic acid (or 17.05 g. of α-chlorophenylacetic acid) isintroduced dropwise in 60 ml. of acetone. The mixture is stirred foranother hour at 56° and allowed to stand for 24 hours. The acetone isdistilled off, the residue is dissolved in 1 1. of water, the solutionis washed several times with ether and acidified with HCl to pH 4, thusobtainingα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid; diisopropylamine salt, m.p. 165°-168°.

b. One gram ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acidis dissolved in 20 ml. of ether and mixed dropwise with etherdiazomethane solution until the mixture assumes a permanent yellowcoloring. After evaporation, the methyl ester ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acidis obtained.

c. 5 g. ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acidis dissolved in 200 ml. of saturated ethanolic hydrochloric acid; themixture is allowed to stand for 12 hours at room temperature, refluxedfor 2 hours, and evaporated. The residue is dissolved in water, theaqueous solution is adjusted to pH 8 with 1N NaOH, and extracted withethyl acetate. The product is dried and evaporated, thus obtaining theethyl ester ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid.

EXAMPLE 10

At 40°, 30 g. of chloroform is added dropwise to a mixture of 23.9 g. of1-p-hydroxyphenol-1,2,3,4-tetrahydro-4-quinol-one, 80 g. of acetone,and21 g. of pulverized KOH. The mixture is reflexed for 12 hours,evaporated, the residue mixed with water, washed with ether, acidifiedto pH 5, and extracted with ether. The ether solution is extracted withdilute sodium carbonate solution, the latter is washed with ether, thenagain acidified and extracted with ether. The ether extracts are driedover sodium sulfate and evaporated, thus obtaining2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid.

EXAMPLE 11

30.1 g. of the ethyl ester of α-4-(4-aminophenoxy)-phenoxypropionic acid(obtainable by reacting 4-(4-nitrophenoxy)-phenol with the ethyl esterof 2-chloropropionic acid to obtain the ethyl ester ofα-4-(4-nitrophenoxy)-phenoxypropionic acid and subsequent reduction ofthe nitro group), 34.5 g. of 1,5-dibromopentane, and 27 g. of K₂ CO₃ arerefluxed under agitation in 400 ml. of n-butanol for 24 hours. Then, themixture is filtered, the solvent distilled off, the residue mixed withwater and extracted with chloroform. The extract is dried andevaporated, thus producing the ethyl ester ofα-4-(4-piperidinophenoxy)-phenoxypropionic acid. Free acid, m.p.160°-162°.

EXAMPLE 12

A mixture of 23.7 g. of the isobutyl ester of2-(4-aminophenoxy)-propionic acid, 23 g. of 1,5-dibromopentane, 14 g. ofNa₂ CO₃, and 100 ml.of acetonitrile is refluxed under agitation for 48hours. The mixture is filtered, evaporated, the residue taken up indilute hydrochloric acid, washed with ether, made alkaline with dilutesolution of sodium hydroxide,extracted with ether, dried, evaporated,and the product thus obtained is the isobutyl ester of2-(4-piperidinophenoxy)-propionic acid.

EXAMPLE 13

34.7 g. of the ethyl ester of α-phanyl-α-4-(4-aminophenyl)-phenoxyaceticacid is refluxed in350 ml. of n-butanol together with 15 g. of1,5-dichloropentane and 15 g. of pulverized K₂ CO₃ for 15 hours. Themixture is then cooled, filtered, the butanol is distilled off, theresidue disolved in 150 ml. ofbenzene and refluxed for 2 hours with 10ml. of acetic anhydride. The reaction mixture is cooled, washed with 1NNaOH, and extracted with 20 percent HCl. The aqueous hydrochloric acidsolution is rendered alkaline, extracted with ether, the ether phasewashed neutral with water, dried, and evaporated, thus obtaining theethyl ester of α-phenyl-α-4-(4-piperidinophenyl)-phenoxyacetic acid,m.p. 126°-128°.

EXAMPLE 14

A solution of 35.7 g. of the methyl ester of2-methyl-2-p-(N-2-carboxyethylanilino)-phenoxypropionic acid (obtainableby reacting the methyl ester of 2 -methyl-2-(p-anilinophenoxy)-propionicacid with propiolactone) in 800 ml. of acetic acid and 55 ml. of aceticanhydride is combined at 90° with a solution of 16 g. of zinc chloridein 165 ml. of acetic anhydride. The mixture is then refluxed for 10minutes, immediately poured into 2.5 l. of water, extracted withether,and the usual working up operation yields the methyl ester of2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid,m.p. 76°-78°.

EXAMPLE 15

A mixture of 35.8 g. of the ethyl ester of2-methyl-2-[p-(1-hydroxy-3-phenoxypropyl)-phenoxy]-propionic acid[obtainable by reacting the ethyl ester of 2-methyl-2-phenoxypropionicacid with 3-chloropropionyl chloride in the presence of AlCl₃, reactingthe thus-produced ethyl ester of2-methyl-2-p-(3-chloropropionyl)-phenoxypropionic acid with Naphenolate, and reducing the obtained ethyl esterof2-methyl-2-p-(3-phenoxypropionyl)-phenoxypropionic acid with NaBH₄[and 200 ml. of 48% hydrobromic acid is refluxed for 3 hours underagitation. The mixture is then cooled, extracted with ethyl acetate, andthe usual working up operation yields the ethyl ester of2-methyl-1-p-(4-chromanyl)-phenoxypropionic acid.

EXAMPLE 16

A mixture of 4.21 g. of the ethyl ester of2-methyl-2-p-(1-o-hydroxyphenol-3-bromopropyl)-phenoxypropionic acid[obtainable by reacting 2,4'-dihydroxybenzophenone with malonic acid,decarboxylation to 3-o-hydroxyphenyl-3-p-hydroxyphenylacrylic acid,reduction with LiAlH₄ to the alcohol, hydrogenation to3-o-hydroxyphenyl-3-p-hydroxyphenylpropanol, reaction with the ethylesterof 2-bromoisobutyric acid to the ethyl ester of2-methyl-2-p-(1-o-hydroxyphenyl-3-hydroxypropyl)-phenoxypropionic acid,and reaction with PBr₃ ], 0.7 g. of sodium ethylate, and 100 ml. ofabsolute ethanol is refluxed for 10 hours, then evaporated and worked upwith ethyl acetate and water, thus obtaining the ethyl ester of2-methyl-2-p-(4-chromayl-phenoxypropionic acid.

EXAMPLE 17

2g. ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetonitrile(obtainable from 4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenol andα-bromo-α-phenylacetonitrile) is refluxed with 2 g. of KOH in 20 ml. ofethanol and 2 ml. of water for 40 hours. The mixture is evaporated,combined with water, extracted with ether, hydrochloric acid is added topH 5, and the product thus obtained isα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid; diisopropyllamine salt, m.p. 165°-168°.

EXAMPLE 18

10 g. ofα-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetonitrileis refluxed with60 ml. of acetic acid and 60 ml. of concentratedhydrochloric acid for 2 hours under nitrogen. The mixture is theevaporated, dissolved in dilute NaOH, extracted with ether, hydrochloricacid is added to pH 5, and the product thus obtained isα-p-chlorophenyl-α -4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid;diisopropylamine salt, m.p. 155°-158°.

EXAMPLE 19

3g. ofα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetamide(obtainable from 4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenolandα-bromophenylacetamide) and 5g. of KOH are refluxed in 100 ml. ofethanolfor 3 hours under nitrogen. The mixture is then evaporated, mixed withwater, extracted with ether, hydrochloric acid is added to pH 4, and thethus-obtained product isα-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid; diisopropylamine salt, m.p. 165°-168°.

EXAMPLE 20

10 g. ofα-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetylchloride (obtainable from the acid and SOCl₂) is heated with 100 ml. ofabsolute n-propanol for 3 hours to 95°. The mixture is then evaporated,the residue combined with dilute sodium hydroxide solution, and theaqueous solution extracted with ether. The ether solution is washedtwice with dilute NaOH and twice with water, dried, evaporated to removethe ether, and the n-propyl ester ofα-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid isthus obtained.

EXAMPLE 21

9 g. of α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetylchloride is dissolved in 100 ml. of absolute tetrahydrofuran and mixedwith 3 g. of potassium tert.-butylate. The mixture is stirred for 30minutes at room temperature, filtered, the filtrate evaporated, and theproduct worked up as described in Example 14, thus producing thetert.-butyl ester ofα-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid.

EXAMPLE 22

Under agitation, a solution of 18.15 g. ofN-chloro-1,2,3,4-tetrahydro-4-quinolone in 30 ml. of concentratedsulfuricacid is added dropwise within 10 minutes to a mixture of 26.25g. of α-p-chlorophenyl-α-phenoxyacetic acid, 14 g. of iron(II) sulfateheptahydrate, 15 ml. of concentrated sulfuric acid, and 6 ml. of water.The mixture is stirred for another 15 minutes at 20°, then poured ontoice water, washed with ether, sodium hydroxide solution is added to pH5,and the mixture is extracted with chloroform. From the extract, afterevaporation,α-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid is obtained, m.p. 180°-185°.

EXAMPLE 23

14.7 g. of 1,2,3,4-tetrahydro-4-quinolone and 3.9 g. of NaNH₂ areagitated for one hour at 100° under a nitrogen atmosphere. Then, 38.65g. of the disodium salt of α-p-chlorophenyl-α-p-sulfophenoxyacetic acidis added thereto (obtainable by the sulfonation ofα-p-chlorophenyl-α-phenoxyacetic acid) together with another 15 g. of1,2,3,4-tetrahydro-4-quinolone, and the mixture is heated for 12 hoursunder agitation to 120°. After cooling, the mixture is combined withwater, washed with ether, and the aqueous phase is adjusted to pH 5,thus producingα-p-chloropheny-α-p-(4-oxo-1,2,3,4-tetrahydroquinoline)-phenoxyaceticacid, m.p. 180°-185°.

EXAMPLE 24

A mixture of 31.4 g. of α-p-chlorophenyl-α-p-aminophenoxyaceticacidhydrochloride, 14.7 g. of 1,2,3,4-tetrahydro-4-quinolone, and 1 g. ofAlCl₃ is heated in an autoclave for 48 hours to 200°. After cooling andworking up the mixture as usual,α-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid is obtained, m.p. 180°-185°.

EXAMPLE 25

A mixture of 15 g. of 4-chromanol, 20.8 g. of the ethyl ester of2-methyl-2-phenoxypropionic acid, and 13.4 g. of AlCl₃ in 200 ml. ofchlorobenzene is agitated overnight at 25°. Then, the mixture is pouredon ice water, the organic phase is washed with NaHCO₃ solutionand withwater, the solvent is distilled off, the mixture dissolved in benzeneand filtered over Al₂ O₃, thus obtaining the ethyl esterof2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid.

EXAMPLE 26

A solution of 2 g. of 2-methyl-2-p-(3-chromen-4-yl)-phenoxypropionicacid [obtainable by reacting4-chromanone withp-(2-carboxy-2-propoxy)-phenylmagnesium bromide in tetrahydrofuran andsubsequently working up the product with HCl] in 50 ml. of dioxane ishydrogenated on 0.2 g. of 5 percent palladium-charcoal until thehydrogen absorption has ceased. The reaction product is filtered,evaporated, and the thus-obtained product is2-methyl-2-p-(4-chromanyl)-phenoxypropionic acid; cyclohexylamine salt,m.p. 196°-198°.

EXAMPLE 27

A mixture of 0.78 g. of NaNH₂ and 3.76 g. of2-phenyl-2-p-(4-thiochromanyl)-phenoxyacetic acid in 30 ml. of THF isgradually heated to 70° under agitation, then cooled to 20°,20 ml. ofHMPA is added thereto, the mixture cooled to 0°, and, at 0°, 1.5 g. ofmethyl iodide is added dropwise thereto. Thereafter, the mixture isheated for 3 hours under agitation to 70°, evaporated and worked up asusual, thus obtaining 2-phenyl-2-p-(4-thiochromanyl)-phenoxypropionicacid; Na salt, m.p. 200°-202°.

EXAMPLE 28

At -40°, 50 mg. of iron(III) nitrate is dissolved in 100 ml, of liquidammonia and then 2.3 g. of Na is likewise dissolved therein underagitation. After two hours of stirring, 3.41 g. of2-phenyl-2-p-(4-chromanyl)-phenoxyacetonitrile is added thereto, themixture is stirred for 30 minutes, and then 19.2 ml. of dimethyl sulfateis added dropwise within one hour. The mixture is further agitated at-35° overnight and then mixed dropwise with another 10 ml. of dimethylsulfate. After the ammonia has evaporated, the residue is combined withwater and extracted with ether. The crude2-phenyl-2-p-(4-chromanyl)-phenoxypropionitrile obtained afterevaporationof the ether is refluxed for 40 hours with 3 g. of KOH in 30ml. of ethanoland 3 ml. of water. The mixture is then concentrated byevaporation, mixed with water, extracted with ether, and hydrochloricacid is added to pH 5, thus obtaining2-phenyl-2-p-(4-chromanyl)-phenoxypropionic acid; cyclohexylamine salt,m.p. 190°-193°.

The following examples relate to pharmaceutical preparations containingtheeffective agents of general Formula I and/or the physiologicallyacceptablesalts thereof:

EXAMPLE A - TABLETS

A mixture consisting of 100 kg. ofα-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid, 400 kg. of lactose, 120 kg. of potato starch, 20 kg. of talc, and10 kg. of magnesium stearate is pressed to tablets in the usual manner,so that each tablet contains 100 mg. of the effective agent.

EXAMPLE B -DRAGEES

Analogously to Example A, tablets are pressed which are thereaftercovered with a coating consisting of sugar, corn starch, talc, andtragacenth.

Analogously, tablets and dragees can be obtained which contain one ormore of the remaining effective agents of Formula I and/or thephysiologically acceptable salts thereof.

The preceding examples can be repeated with similar success bysubstitutingthe generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertainthe essential characteristics of this invention, and withoutdeparting fromthe spirit and scope thereof, can make various changes andmodifications ofthe invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of the formula ##SPC10##wherein R₁ isH or alkyl of 1-4 carbon atoms, R₂ is H, or when R₄ is Q, H or alkyl of1-4 carbon atoms, R₃ is phenyl or chlorophenyl and R₄ is1,2,3,4-tetrahydroquinolino, 1-R₅ -1,2,3,4-tetrahydro-4-quinolyl or Q,wherein R₅ is H or alkyl of 1-4 carbon atoms and Q is4-oxo-1,2,3,4-tetrahydroquinolino,4-hydroxy-1,2,3,4-tetrahydroquinolino, or1-phenyl-1,2,3,4-tetrahydro-4-quinolyl, and the physiologicallyacceptable salts thereof.
 2. A compound of claim 1 wherein R₁ is H, CH₃or C₂ H₅ and R₂ is H or CH₃.
 3. A compound of claim 1 wherein R₃ isphenyl, m-chlorophenyl or p-chlorophenyl.
 4. A compound of claim 1wherein R₄ is 1,2,3,4-tetrahydroquinolino.
 5. A compound of claim 1wherein R₄ is 1-R₅ -1,2,3,4-tetrahydro-4-quinolyl, wherein R₅ is H oralkyl of 1-4 carbon atoms.
 6. A compound of claim 5 wherein R₃ is,phenyl, m-chlorophenyl or p-chlorophenyl.
 7. A compound of claim 1wherein R₄ is 4-hydroxy- or 4-oxo-1,2,3,4-tetrahydroquinolino.
 8. Acompound of claim 1 wherein R₄ is,1-phenyl-1,2,3,4-tetrahydro-4-quinolyl.
 9. A compound of claim 7,wherein R₁ is H, CH₃ or C₂ H₅ and R₂ is H or CH₃.
 10. A compound ofclaim 7 wherein R₃ is phenyl, m-chlorophenyl or p-chlorophenyl.
 11. Acompound of claim 1,α-phenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxy-acetic acid,α-phenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid ethylester, α-phenyl-α-4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acid,α-phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid, α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid, α-p-chlorophenyl-α-4-(1,2,3,4-tetrahydroquinolino)-phenoxy-aceticacid ethyl ester,α-p-chlorophenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyaceticacid, α-phenyl-α -p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid, 2-phenyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid ethyl ester,α-p-chloro-phenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid.
 12. A compound of claim 7 wherein R₄ is4-oxo-1,2,3,4-tetrahydroquinoline.
 13. A compound of claim 7,α-p-chlorophenyl-α-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxyaceticacid.
 14. 2-Phenyl-2-p-(4-oxo -1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid ethyl ester, a compound of claim
 1. 15. α-Phenyl-α-4(1,2,3,4-tetrahydroquinolino)-phenoxyacetic acid in the formof the diisopropylamine salt, a compound of claim
 1. 16. α-Phenyl-α-4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxyacetic acidin the form of the diisopropylamine salt, a compound of claim
 1. 17. Acompound of the formula ##SPC11##wherein R₁ and R₂ each are H or alkylof 1-4 carbon atoms and R₄ is 4-hydroxy- or4-oxo-1,2,3,4-tetrahydroquinolino, and the physiologically acceptablesalts thereof.
 18. A compound of claim 17,2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acid.
 19. Acompound of claim 17,2-methyl-2-p-(4-oxo-1,2,3,4-tetrahydroquinolino)-phenoxypropionic acidmethyl ester.
 20. A compound of claim 17,2-methyl-2-p-(4-hydroxy-1,2,3,4-tetrahydroquinolino)-phenoxypropionicacid methyl ester.